Perspective from ECCMID Part III: CDI synthetic “repoopulation” (bacteriotherapy) closer than you think & “CA-CDI” still pie in the sky

As our understanding of the importance of a happy, healthy microbiota develops, it seems increasingly clear to me that bacteriotherapy (administration of a controlled multi-species dose of bacteria) is a real prospect for the treatment of CDI (and most likely other conditions). This is illustrated by the dramatic effectiveness of faecal microbiota transplantation (FMT) for recurrent CDI. FMT is pretty crude, in every sense; synthetic FMT would be safer and more palatable. But I hadn’t realized how far the research towards available bacteriotherphy for CDI had advanced. Dr Trever Lawley gave an expert overview of his research programme, which is pointed in this direction.

Dr Lawley began by describing the human microbiota as a fingerprint: it’s consistent and unique. The microbiota is highly organized, to reflect its function, resulting in microenvironments. Antibiotics are like an atomoic bomb, resulting in huge perturbation of the gut microbiota. The idea of bacteriotheraphy to redress the balance is not new. Pioneers of bacteriotherapy (aka “repoopulation”) for CDI date back to at least 1989.

So, which bacteria get the nod to be included in the synthetic mix? It’s not an easy question, since examining the massively populous human microbiota is a daunting prospect and requires the application of novel tools (see Fig 1 of this excellent open-access review for a useful summary of the methods to examine the human microbiota and microbiome). Human trials and mouse model indicate that single species theraphy and probiotics are equivocal at best. These are blunt weapons to complement the nuclear fall out of the antibiotic A bombs! Dr Lawley’s reaseach has found an irreducible minimum of 6 species that are necessary for effective bacteriotherapy (in mice at least). Now all that is required is to find a common growth medium…oh, and do some humans trials!

A number of speakers contributed to the debate on whether “community-acquired” CDI is on the rise. Dr Scott Weese outlined the potential for foodborne risk of CDI, beginning with a ‘disclosure’ that we can all relate to: “I like to eat but I don’t like foodborne illness”! C. difficile is present in food animials (especially young ones) and strains are shared with humans. Rates of carriage are low, but Dr Weese made a good point on cumulative exposure. If 2% of burgers are C. difficile contaminated, I eat C. difficile on my 98th burger (not exactly, but you get the point). Plus, C. difficile spores can survive usual cooking times (which is not so relevant for me: I like my burger meat rare)! The carriage of C. difficile in animals combined with the high carriage of C. difficile in small human animals means that exposure to C. difficile is probably a daily event. But is this a risk? For a healthy 25 year old in the community, probably no. For a haematology inpatient, probably yes.

Dr Marjolein Hensgens considered whether CDI is still primarily nosocomial. The distinction of community vs. hospital onset is easy, but community vs. hospital acquisition is much more challenging and epidemiological disitinctions are approximate at best. For example, in the UK, a “Trust-apportioned” (=hospital acquired) case requires a specimen from an inpatient who has been in the same hospital for at least 4 days. Any readmission (even if they were in the hospital the previous week) is considered “non Trust-apportioned”, but it’s important to remember that this is not the same as “community-acquired”. The fact that the Trust-apportioned and non Trust-apportioned cases track each other so closely in the UK reductions suggests that almost all cases were healthcare-associated (Figure 1).

Figure 1: the number of CDI cases reported to Public Health England, defined as “Trust-apportioned” or “non Trust-apportioned” from 2007 onwards.

An important US study suggested a stepwise increase in CA-CDI. However, this apparent increase could be explained by a number of other factors. Firstly, a high proportion of patients with apparent CA-CDI actually have had healthcare exposoure of some kind if you look hard enough (82% in this study). So this upward trend in “CA-CDI” could very well be HA-CDI with unrecognized healthcare exposures. Secondly, it is difficult to know whether there have been any changes in the number of diarrhoeal stools tested in the community. Infectious diarrohea has always been common in the community, but is rarely tested for CDI. Thirdly, comparing the epidemiology of patients who develop CDI in the community with those who develop CDI in hospitals could result in a misleading picture. A more appropriate comparator would be patients who have non-CDI diarrhea in the community. Finally, does WGS prove that hospital acquisition of CDI is now rare? No, it only proves that transmission from known symptomatic CDI cases is less frequent than you may expect. There are many other sources for hospital acquisition of CDI, not least asymptomatic carriers. We’re surrounded by C. difficile so of course a degree of CA-CDI occurs. But is it increasing? I still think no – or at least, not rapidly due to phase-shift in epideimogogy (that we saw with the emergence of CA-MRSA in the late 1990s).

5 thoughts on “Perspective from ECCMID Part III: CDI synthetic “repoopulation” (bacteriotherapy) closer than you think & “CA-CDI” still pie in the sky”

Jon,
I’ve often thought that this approach would be effective in a number of scenarios. When I conducted a two year longitudinal study on the nasal prevalence of staphyolococci in nursing students, we discovered not only a high number of different species, but also a changing nasal flora in individuals from one time wave (~3 months) to the next time wave. I have often hypothesized that “planting” healthy staph flora in the nasal (and perhaps other areas of the body) region could eliminated the issue of MRSA. Of course, further investigation into protective species should be conducted to followup these ideas. Great synopsis of CA-CDI!

The UK approach of hospital-association is a poor guide to where infection is acquired. It does not deal at all with the 40% of hospitalised over 65s who are readmitted to hospital within 6 months. this is impossible to look at in tertiary centres and metropolitan areas or to extract from passive reports. In rural “islands” with 1 hospital and known residential facilities it is possible to look properly, although it is not possible to check for other family members hospital admissions. When you do this and apply the extended ECDC/CDC agreed 90 day past healthcare exposure rules the community and hospital-acquired cases still show the same ribotypes. Assuming good hospital C diff control with no clustering this then raises the question whether we are dealing with community not hospital acquistion in many cases …. in England now!

Thanks Rod, agree that tracing healthcare exposures can be very tricky retrospectively. A recent study showed that >80% of apparent “CA-CDI” had healthcare exposures if you look closely enough. I’m not sure we can assume that the UK is dealing mainly with community-acquired CDI cases now; there are plenty of reservoirs for hospital transmission that were not evaluated in the Oxford NEJM study, not least asymptomatic carriers.